Key result
Structure-based drug design has led to the development of novel fibrinolysis inhibitors, including potent ligands targeting lysine binding sites and active site inhibitors of plasmin.
Why the study?
Approved antifibrinolytic agents were developed in the 1960s without structural insight into their targets, despite hyperfibrinolytic situations causing life-threatening bleeding especially during cardiac surgery.
Recent structural insights into plasminogen and plasmin have facilitated the development of novel, highly potent fibrinolysis inhibitors to prevent and treat life-threatening bleeding.
May advance bleeding management options; leaves open clinical translation of these preclinical ligands.
Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crystal structures of the main antifibrinolytic targets, the lysine binding sites on plasminogen's kringle domains, and plasmin's serine protease domain greatly contributed to the structure-based drug design of novel inhibitor classes. Two series of ligands targeting the lysine binding sites have been recently described, which are more potent than the most-widely used antifibrinolytic agent, tranexamic acid. Furthermore, four types of promising active site inhibitors of plasmin have been developed: tranexamic acid conjugates targeting the S1 pocket and primed sites, substrate-analogue linear homopiperidylalanine-containing 4-amidinobenzylamide derivatives, macrocyclic inhibitors addressing nonprimed binding regions, and bicyclic 14-mer SFTI-1 analogues blocking both, primed and nonprimed binding sites of plasmin. Furthermore, several allosteric plasmin inhibitors based on heparin mimetics have been developed.
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Steinmetzer et al. (2019) conducted a review in Hyperfibrinolytic situations and bleeding. Fibrinolysis Inhibitors was evaluated. Structure-based drug design has led to the development of novel fibrinolysis inhibitors, including potent ligands targeting lysine binding sites and active site inhibitors of plasmin.
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